Vol. 282, Issue 1, 309-317, 1997

Extracellular Mg⁺⁺ Manipulation Prevents the Proarrhythmic Activity of Cromakalim in Ischemic/Reperfused Diabetic Hearts¹

Arpad Tosaki and Dipak K. Das

University of Connecticut Health Center, School of Medicine, Farmington, Connecticut

Cromakalim, an adenosine triphosphate-sensitive potassium channel opener, shows proarrhythmic activity at moderate doses (1-10 µmol/liter) in the ischemic and reperfused myocardium. We studied the effects of extracellular Mg⁺⁺ ([Mg⁺⁺]) on the incidence of reperfusion-induced ventricular fibrillation and ventricular tachycardia in isolated working hearts (n = 12 in each group) subjected to 20 min of global ischemia followed by 30 min of reperfusion, a model eliciting a low incidence of reperfusion arrhythmias, obtained from 8-wk streptozotocin-induced diabetic rats. Cromakalim, at a concentration of 3 µmol/liter, perfused 5 min before the induction of ischemia and throughout reperfusion increased the incidence of ventricular fibrillation and ventricular tachycardia from their drug-free diabetic control values of 25 and 42% ([Mg⁺⁺] = 1.2 mmol/liter) to 92% (P < .05) and 100% (P < .05), respectively. Glibenclamide at a concentration of 3 µmol/liter prevented the proarrhythmiac activity of cromakalim. Increasing concentration of [Mg⁺⁺] to 2.4, 3.6 and 4.8 mmol/liter in the perfusion buffer, the arrhythmogenic effect of cromakalim was also abolished. Thus, with 2.4, 3.6 and 4.8 mmol/liter of [Mg⁺⁺] perfused before the administration of cromakalim and the onset of ischemia, the incidence of reperfusion-induced ventricular tachycardia was reduced from 92% (in cromakalim treated group) to 67%, 42% (P < .05), and 25% (P < .05), respectively. The incidence of reperfusion-induced ventricular tachycardia showed the same pattern. Elevated [Mg⁺⁺] prevented the cromakalim-induced cellular Na⁺ gain and K⁺ loss, measured by atomic absorption spectrophotometer. [Mg⁺⁺] could prevent the proarrhythmic activity of cromakalim, and the use of cromakalim as an antihypertensive or antiischemic agent may be of particular concern in the population of postischemic diabetic subjects who are known to be at high risk of sudden coronary death.